We propose an ambitious program of collaborative research to identify and characterize molecular mechanisms responsible for altered programs of inflammatory gene expression that contribute to insulin resistance. We will capitalize on our recent discoveries of unexpected roles of GPS2 and the nuclear receptor co-repressors NCoR and SMRT in regulation of inflammatory signaling pathways in macrophages and adipocytes. We will extend studies of novel mechanisms mediating the recruitment of pro-inflammatory macrophages into adipose tissue that have clear translational potential. We will utilize newly developed technologies to characterize the genomic locations and functions of PPARy in adipose tissue macrophages in vivo to determine mechanisms by which macrophage PPARy contributes to insulin-sensitizing functions of thiazolidinediones. We will investigate the roles o 3 dimensional chromatin interactions and non-coding RNAs in positive and negative regulation of inflammatory gene expression. Overall, the proposed studies are expected to lead to new insights into mechanisms underlying obesity-associated insulin resistance that will facilitate development of new approaches for the prevention and treatment of type 2 diabetes.